My laboratory researches neurobiological mechanisms underlying obesity. First, we discovered neuro-adipose junctions between white adipocytes and sympathetic neurons that constitute a peripheral effector arm of leptin action in the brain (1). Moreover, we discovered that this efferent arm is negatively regulated by Sympathetic neuron-Associated Macrophages (SAMs) that import NE via the Slc6a2 transporter resulting in its clearance. Abrogation of SAM function promotes long-term mitigation of obesity independently of food intake (2). These findings inspired the development of a new class of anti-obesity compounds named sympathofacilitators, designed not to enter the brain. Consequently, they do not have the typical cardiovascular side effects of centrally acting sympathomimetic drugs (3). Sympathofacilitator drugs act as an energy sink by coupling thermogenesis to active heat dissipation via the beta2 adrenergic receptor, independently of food intake. Whereas druggability intersects our discovery path, the overall focus of this talk are the fundamental aspects of sympathetic-nerve biology in the context of obesity and metabolic dysfunction. We have coined the term Neuroimmunometabolism to designate the study of the crosstalk between immune cells and neurons controlling whole-body metabolism. Neuroimmunometabolic mechanisms linking inflammation to SNS neuronal function, and leptin resistance will be discussed (4).